Ganoderma lucidum (Reishi) Inhibits Cancer Cell Growth and Expression of Key Molecules in Inflammatory Breast Cancer

Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico.
Nutrition and Cancer (Impact Factor: 2.32). 09/2011; 63(7):1085-94. DOI: 10.1080/01635581.2011.601845
Source: PubMed


Inflammatory breast cancer (IBC) is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the lymphatic system and absence of a palpable tumor mass. Different from other metastatic breast cancer cells, IBC cells invade by forming tumor spheroids that retain E-cadherin-based cell-cell adhesions. Herein we describe the potential of the medicinal mushroom Ganoderma lucidum (Reishi) as an attractive candidate for anti-IBC therapy. Reishi contains biological compounds that are cytotoxic against cancer cells. We report the effects of Reishi on viability, apoptosis, invasion, and its mechanism of action in IBC cells (SUM-149). Results show that Reishi selectively inhibits cancer cell viability although it does not affect the viability of noncancerous mammary epithelial cells. Apoptosis induction is consistent with decreased cell viability. Reishi inhibits cell invasion and disrupts the cell spheroids that are characteristic of the IBC invasive pathology. Reishi decreases the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB), and invasion and metastasis (MMP-9), whereas it increases the expression of IL8. Reishi reduces BCL-2, BCL-XL, E-cadherin, eIF4G, p120-catenin, and c-Myc protein expression and gelatinase activity. These findings suggest that Reishi is an effective anti-IBC therapeutic.

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    • "Ganoderma lucidum (also known as Ling-Zhi or Reishi) is a medicinal mushroom that is widely appreciated as a traditional Chinese medicine throughout the world. It has been well documented that Reishi possesses a broad range of pharmacological properties including antitumor [1], immuno modulatory [2], and anti-inflammatory activities [3]. LZ-8 is an immunomodulatory protein that can be isolated from Reishi. "
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    ABSTRACT: - LZ-8, an immunomodulatory protein isolated from Ganoderma lucidum (also known as Ling-Zhi or Reishi), has been shown to promote cell proliferation and IL-2 production in T cells. In this study, we show that LZ-8 induces the expansion of both murine and human CD4(+) T cells into FOXP3(+) regulatory T (Treg) cells. LZ-8 treatment was found to stimulate a 4-fold and a 10-fold expansion in the Treg populations of murine and human primary CD4(+) T cells, respectively. In addition, the expression of CTLA-4 and IL-10 was induced in LZ-8-treated CD4(+) T cells. Using neutralizing antibodies and gene-deficient T-cell lines, we also found that LZ-8 promotes Treg expansion through a CD45-mediated signaling pathway and that the CD18-dependent induction of IL-2 was involved in Treg formation and IL-10 production. The suppressive activity of LZ-8 was confirmed using a murine model of DSS-induced colitis; the disease was alleviated by the adoptive transfer of LZ-8-treated CD4(+) T cells. In conclusion, a new regulatory function for LZ-8 was identified, and the molecular mechanisms underlying this function were elucidated.
    Evidence-based Complementary and Alternative Medicine 06/2013; 2013:513542. DOI:10.1155/2013/513542 · 1.88 Impact Factor
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    • "Using the established IBC cell model, SUM-149 cells, we previously published that Reishi selectively reduced cancer cell viability and invasion [9]. To test whether Reishi treatment affects the expression of genes specifically involved in the PI3K/AKT/mTOR pathway, we performed PI3K/AKT signaling RT2 Profiler PCR arrays in SUM-149 cells treated with vehicle or 0.5 mg/mL Reishi for 3 hours. "
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    ABSTRACT: The medicinal mushroom (Reishi) was tested as a potential therapeutic for Inflammatory Breast Cancer (IBC) using and IBC models. IBC is a lethal and aggressive form of breast cancer that manifests itself without a typical tumor mass. Studies show that IBC tissue biopsies overexpress E-cadherin and the eukaryotic initiation factor 4GI (eIF4GI), two proteins that are partially responsible for the unique pathological properties of this disease. IBC is treated with a multimodal approach that includes non-targeted systemic chemotherapy, surgery, and radiation. Because of its non-toxic and selective anti-cancer activity, medicinal mushroom extracts have received attention for their use in cancer therapy. Our previous studies demonstrate these selective anti-cancer effects of Reishi, where IBC cell viability and invasion, as well as the expression of key IBC molecules, including eIF4G is compromised. Thus, herein we define the mechanistic effects of Reishi focusing on the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a regulator of cell survival and growth. The present study demonstrates that Reishi treated IBC SUM-149 cells have reduced expression of mTOR downstream effectors at early treatment times, as we observe reduced eIF4G levels coupled with increased levels of eIF4E bound to 4E-BP, with consequential protein synthesis reduction. Severe combined immunodeficient mice injected with IBC cells treated with Reishi for 13 weeks show reduced tumor growth and weight by ∼50%, and Reishi treated tumors showed reduced expression of E-cadherin, mTOR, eIF4G, and p70S6K, and activity of extracellular regulated kinase (ERK1/2). Our results provide evidence that Reishi suppresses protein synthesis and tumor growth by affecting survival and proliferative signaling pathways that act on translation, suggesting that Reishi is a potential natural therapeutic for breast and other cancers.
    PLoS ONE 02/2013; 8(2):e57431. DOI:10.1371/journal.pone.0057431 · 3.23 Impact Factor
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    ABSTRACT: Dietary soy is thought to be cancer preventive; however, the beneficial effects of soy on established breast cancer is controversial. We recently demonstrated that dietary daidzein or combined soy isoflavones (genistein, daidzein, and glycitein) increased primary mammary tumor growth and metastasis. Cancer promoting molecules, including eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E, were upregulated in mammary tumors from mice that received dietary daidzein. Herein, we show that increased eIF expression in tumor extracts of mice following daidzein diets, is associated with protein expression of mRNAs with internal ribosome entry sites (IRES) that are sensitive to eIF4E and eIF4G levels. Results with metastatic cancer cell lines show that some of the effects of daidzein in vivo can be recapitulated by the daidzein metabolite equol. In vitro, equol, but not daidzein, upregulated eIF4G, without affecting eIF4E or its regulator, 4E binding protein (4E-BP), levels. Equol also increased metastatic cancer cell viability. Equol specifically increased the protein expression of IRES containing cell survival and proliferation promoting molecules, and upregulated gene and protein expression of the transcription factor c-Myc. Moreover, equol increased the polysomal association of mRNAs for p 120 catenin and eIF4G. The elevated eIF4G in response to equol was not associated with eIF4E or 4E-BP in m7GTP cap co-capture assays or co-immunoprecipitations. In dual luciferase assays, IRES-dependent protein synthesis was increased by equol. Therefore, upregulation of eIF4G by equol may result in increased translation of pro-cancer mRNAs with IRESs, and thus, promote cancer malignancy.
    Journal of Biological Chemistry 10/2012; 287(50). DOI:10.1074/jbc.M112.393470 · 4.57 Impact Factor
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